Aluminum-Catalyzed Cross-Coupling of Silylalkynes with Aliphatic C–F Bonds

Abstract

We report the generation of aliphatic and benzylic acetylenes via reaction of primary, secondary, and tertiary aliphatic fluorides with various trimethylsilyl acetylides. These reactions are catalyzed by Al and B Lewis acids, most effectively by the extremely fluorophilic tris(pentafluorophenyl)alane, representing the first example of catalytic incorporation of alkynes into aliphatic C-F positions. The fluorophilicity of the catalysts gives rise to fluorine selectivity over other halogens, allowing orthogonal reactivity pathways.

Nucleophilic Substitution of Aliphatic Fluorides via Pseudohalide Intermediates

“…Such catalysts have low functional group tolerance, with their reactivity either arrested or hindered in the presence of alcohol, amine, ester, carboxylic acid, carbonyl, ether, and nitrile groups ( inter alia). Furthermore, Lewis acid catalyst strategies that proceed by carbocation pathways are prone to rearrangement and elimination reactions and Friedel–Crafts reactivity, resulting in poor tolerance of arene solvents ,,,,,,. Indeed, C–F functionalization exploiting Friedel–Crafts reactivity also suffers from poor selectivity and low reactivity with arenes deactivated with electron‐withdrawing groups ,,,,…”

“…A strategy that has recently been exploited to overcome poor reactivity and/or improve selectivity, has been to preinstall silyl groups on coupling partners prior to C−F functionalization ,,,,,. During the functional defluorination reaction, silyl fluoride byproducts act as thermodynamic sinks, driving reactivity.…”

“…Retention of regiochemistry for primary positions ( 3 f – i ) in Lewis acid catalyzed fluoride substitution reactions is challenging in S N 1‐type substitutions . As such, we decided to benchmark the above descried reactions with other halide and pseudohalide sources to determine the origin of the high regioselectivity.…”

“…Under these conditions, exclusive functionalization of the benzyl‐fluoro position in 1 l was observed to generate 3 p in 62 % isolated yield (Figure ) . Similar reactivity preference has been observed in hydrogen‐bonding activated Friedel–Crafts alkylations using benzylic fluorides and aluminium‐catalyzed alkynyl couplings with benzylic fluorides . The ability to selectively target fluoride positions in the presence of alkyl chloro, bromo, and iodo motifs represents a distinct advantage of this methodology over previously reported halodefluorination approaches, and provides the possibility of orthogonal synthetic strategies.…”

Recent Developments on the Use of Group 13 Metal Complexes in Catalysis

“…In addition to the various reactions discussed above, there are severalo ther notable transformationsf irst taking advantage of Al III Lewis acids as catalysts. For instance, the high affinity of aluminuma nd silicon for fluorine was recently exploited through the use of Al(C 6 F 5 ) 3 as catalystf or cross-coupling of silylalkynes with aliphatic fluoridesR F. [93] Ad inuclear aluminum iminopyridine complex (31,S cheme 25) was found to effectively catalyzet he addition of amines to carbodiimides to afford guanidines. [94] Ar elated aluminum iminopyridine pincer complex [95] and its next generation improvement, ab ispyrazolypyridine compound (32 and 33,S cheme 25), [96] can be employed as active catalysts for the electrocatalytic evolution of dihydrogen.…”